Angiogenesis, the development of new blood vessels from the endothelium of a preexisting vasculature, is a critical process in the growth, progression, and metastasis of solid tumors within the host. During physiologically normal angiogenesis, the autocrine, paracrine, and amphicrine interactions of the vascular endothelium with its surrounding stromal components are tightly regulated both spatially and temporally. Additionally, the levels and activities of proangiogenic and angiostatic cytokines and growth factors are maintained in balance. In contrast, the pathological angiogenesis necessary for active tumor growth is sustained and persistent, representing a dysregulation of the normal angiogenic system. Solid and hematopoietic tumor types are particularly associated with a high level of abnormal angiogenesis. More recently, it has become apparent that certain types of leukemia are also influenced by signaling involved in angiogenesis.
Agents that inhibit angiogenesis are useful in treating cancer. Avastin™ (bevacizumab), a monoclonal antibody that binds to Vascular Endothelial Growth Factor (VEGF), has proven to be effective in the treatment of a variety of cancers. Antagonists of the SDF/CXCR4 signaling pathway inhibit tumor neovascularization and are effective against cancer in mouse models (Guleng et al. Cancer Res. 2005 Jul. 1; 65(13):5864-71). The isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3) has completed phase I clinical evaluation as an orally bioavailable angiogenesis inhibitor. NM-3 directly kills both endothelial and tumor cells in vitro and is effective in the treatment of diverse human tumor xenografts in mice (Agata et al. Cancer Chemother Pharmacol. 2005 Jun. 10; [Epub ahead of print]).
Angiogenesis is a feature of other, non-neoplastic disorders. Various ocular disorders, particularly proliferative retinopathies and age-related macular degeneration, and inflammatory disorders, such as rheumatoid arthritis and psoriasis, are marked by increased vascularization of the affected tissue. Anti-angiogenic agents are effective for the treatment of these disorders. Macugen™, an aptamer that binds to VEGF has proven to be effective in the treatment of neovascular (wet) age-related macular degeneration. The success of TNF-alpha antagonists in the treatment of rheumatoid arthritis is partially attributed to anti-angiogenic effects on the inflamed joint tissue (Feldmann et al. Annu Rev Immunol. 2001; 19:163-96).
Arteriogenesis, a process related to but distinct from angiogenesis, occurs when the lumen of a pre-existing vessel increases to form a collateral. After myocardial infarction or peripheral ischemia (e.g., limb, kidney, etc.) arterioles become more significant conductance vessels in order to maintain blood flow after occlusion of the major artery serving the affected tissue. Thus, agents that promote arteriogenesis may be used to treat myocardial infarction and other ischemic events, and may also be used to prevent an ischemic event where a partial arterial occlusion is detected or suspected.
The Notch pathway, and particularly Notch1 and Notch4, participates in angiogenic processes. Notch signalling is generally involved in the regulation of processes as diverse as cellular proliferation, differentiation, specification and survival (Artavanis-Tsakonas et al., 1999). Its complexity in vertebrates is illustrated by the existence of multiple Notch receptor and ligands, each with distinct patterns of expression. In mammals there are four Notch receptors (notch1-4) and five ligands (jagged1, 2 and Dll1, 3 and 4). Mutations of Notch receptors and ligands in mice lead to abnormalities in various organs, from all three germ lines, including the vascular system (Iso et al., 2003). The Notch pathway functions through local cell interactions, the extracellular domain of the ligand, present on the surface of one cell, interacts with the extracellular domain of the receptor on an adjacent cell. This interaction allows the action of two ADAM proteases on the extracellular domain of Notch followed by the action of a γ-secretase on the transmembrane domain releasing the intracellular domain from the cell membrane and allowing it to be directed to the nucleus, where it functions with CSL to activate the expression of transcriptional repressors of the enhancer-of-split family (Mumm & Kopan, 2000).
Arterial versus venous differentiation has long been thought to be mainly dependent on physical factors such as blood pressure and oxygen concentration. Recently, however, the identification of a number of genes that are specifically expressed in arterial or venous endothelial cells well before the onset of circulation, seems to indicate an important role for genetic determination of endothelial cells in the primary differentiation events between arteries and veins. Among these genes are eph-B4, specifically expressed in venous endothelial cells (Adams et al., 1999) and ephrin-B2 (Adams et al., 1999; Gale et al., 2001), notch1 (Krebs et al., 2000), notch4 (Uyttendaele et al., 1996) and dll4 (Shutter et al., 2000), among others, which are specifically expressed in arterial endothelial cells.
Studies with mutations in zebrafish Notch homologues demonstrate the importance of this pathway in regulating the arterial versus venous endothelial differentiation, downstream of vascular endothelial growth factor and sonic-hedgehog and upstream of the ephrin pathway (Lawson et al., 2002), being the earliest genes expressed in an endothelial arterial specific fashion. There is mounting evidence, in both zebrafish and mouse, that Notch function is essential in the establishment of the arterial endothelial cell fate (Lawson et al., 2002; Fischer et al., 2004; Duarte et al., 2004).
It is a goal of the present disclosure to provide agents and therapeutic treatments for modulating angiogenesis, arteriogenesis and vessel identity.